LANOXIN (Page 2 of 7)

Excretion

Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood.

Special Populations

Race differences in digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.

The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance includes age, body weight, and gender. Table 5 that provides the usual daily maintenance dose requirements of LANOXIN Tablets based on creatinine clearance (per 70 kg) is presented in the DOSAGE AND ADMINISTRATION section.

Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.

Pharmacodynamic and Clinical Effects

The times to onset of pharmacologic effect and to peak effect of preparations of LANOXIN are shown in Table 2.

Table 2. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN

Product

Time to Onset of Effecta

Time to Peak Effecta

LANOXIN Tablets

0.5 — 2 hours

2 — 6 hours

LANOXIN Injection/IV

5 — 30 minutesb

1 — 4 hours

a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.

b Depending upon rate of infusion.

Hemodynamic Effects

Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.

Chronic Heart Failure

Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with LANOXIN. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients’ global assessment. In the smaller trial, these trended in favor of a treatment benefit.

The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortality study of 6,801 patients with heart failure and left ventricular ejection fraction ≤0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or LANOXIN, the dose of which was adjusted for the patient’s age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). LANOXIN was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least 1 hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause).

Use of LANOXIN was associated with a trend to increase time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mortality and hospitalization attributed to heart failure.

Table 3. Subgroup Analyses of Mortality and Hospitalization During the First 2 Years Following Randomization

Risk of All-Cause Mortality or All-Cause Hospitalizationa

Risk of HF-Related Mortality or HF-Related Hospitalizationa

n

Placebo

LANOXIN

Relative riskb

Placebo

LANOXIN

Relative riskb

All patients

(EF≤0.45)

6,801

604

593

0.94

(0.88-1.00)

294

217

0.69

(0.63-0.76)

NYHA I/II

4,571

549

541

0.96

(0.89-1.04)

242

178

0.70

(0.62-0.80)

EF 0.25-0.45

4,543

568

571

0.99

(0.91-1.07)

244

190

0.74

(0.66-0.84)

CTR ≤0.55

4,455

561

563

0.98

(0.91-1.06)

239

180

0.71

(0.63-0.81)

NYHA III / IV

2,224

719

696

0.88

(0.80-0.97)

402

295

0.65

(0.57-0.75)

EF <0.25

2,258

677

637

0.84

(0.76-0.93)

394

270

0.61

(0.53-0.71)

CTR >0.55

2,346

687

650

0.85

(0.77-0.94)

398

287

0.65

(0.57-0.75)

EF >0.45c

987

571

585

1.04

(0.88-1.23)

179

136

0.72

(0.53-0.99)

a Number of patients with an event during the first 2 years per 1,000 randomized patients.

b Relative risk (95% confidence interval).

c DIG Ancillary Study.

In situations where there is no statistically significant benefit of treatment evident from a trial’s primary endpoint, results pertaining to a secondary endpoint should be interpreted cautiously.

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